EP0623345B1 - Nouveaux composés de morphine pour administration iontophorétique - Google Patents

Nouveaux composés de morphine pour administration iontophorétique Download PDF

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Publication number
EP0623345B1
EP0623345B1 EP93107160A EP93107160A EP0623345B1 EP 0623345 B1 EP0623345 B1 EP 0623345B1 EP 93107160 A EP93107160 A EP 93107160A EP 93107160 A EP93107160 A EP 93107160A EP 0623345 B1 EP0623345 B1 EP 0623345B1
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European Patent Office
Prior art keywords
morphine
citrate
drug
administration
formulation according
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Expired - Lifetime
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EP93107160A
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German (de)
English (en)
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EP0623345A1 (fr
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Robert L. Stephen
Cesare Bonezzi
Cino Rossi
Silvio Eruzzi
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Physion Srl
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Physion Srl
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Priority to AT93107160T priority patent/ATE178797T1/de
Priority to DE69324476T priority patent/DE69324476T2/de
Priority to ES93107160T priority patent/ES2131083T3/es
Publication of EP0623345A1 publication Critical patent/EP0623345A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis

Definitions

  • the present invention relates to new salts of morphine, for use as analgesic medicament for relief of pain through electromotive administration.
  • Morphine is the first opioid drug to have been isolated in pure forme and is used clinically as drug to achieve relief of nocioceptive pain, too severe to be controlled by peripheral analgesics such as the salicylates. Morphine with a pKa of 8.2 units, is strongly ionised at a normal blood pH of 7.4 units and has a low lipid solubility. Therefore this drug is slow to enter the CNS, a fact that is readily verified by having to wait at least 10 minutes after an iv bolus injection to observe maximum respiratory depression.
  • agonism-antagonism actions at CNS receptor sites As yet very limited, morphine remains the "gold standard" for assessing the efficacy of all other opioid drugs. It is familiar to physicians the world over, very inexpensive and, given in correct dosages for different painful conditions, always exerts a beneficial therapeutic effect with small chance of inducing psychological dependence.
  • Morphine base is soluble 1/5000 in water and 1/250 ethanol, thus necessitating ionised formulations for aqueous injections of reasonably small volumes.
  • Two ionised forms, morphine sulphate and morphine hydrochloride, are available for clinical use in most countries. Both formulations are soluble in water, 1/20-25, and their main physical difference is in their solubilities in ethanol, 1/1000 and 1/50, respectively.
  • morphine - hydrobromide methyl bromide
  • oxide nitrate
  • monobasic phosphate acetate
  • lactate meconate
  • tartrate valerate
  • 6-methylether oleate
  • hyperduric ester-nicotinate
  • hydrochloride - nicotinate hydrochloride - nicotinate
  • morphine is used when oral administration of this agent is presumed ineffectual, classically in post-operative situations. Effective though routine intermittent injections are, they have their disadvantages: blood levels of morphine assume a compound sine-wave shape and, depending upon the frequency and dose of the injections, some patients are alternately obtunded and pain free, or very much alert and in considerable pain.
  • Constant iv infusions with bolus doses on demand resolve the above problem and create others: iv lines occasionally clot and, if sometime later the clot is freed, a patient commencing to feel increasing pain inadvertently receives an excessive dose as a form of bolus injection; in addition, most constant infusions are administered by some form of mechanical pump and more than one patient has died because of "runaway" failure of the pump.
  • Passive transdermal administration of fentanyl has been described by Gale et al (US patent No 4,558,580) and Cleary (US patent No 4,911,916), while Aungst et al (EPA No 85109909.3) claimed a similiar technique for the administration of some 13 opioids and opioid antagonists.
  • Passive transdermal administration of a drug for example by patch application, relies ultimately on the concentration gradient to determine the rate of drug delivery and herein lie the advantages of this form of drug administration: it is the essence of simplicity with no delivery device to malfunction; in theory at least, blood levels of drugs reach a plateau and then maintain constant levels for many hours, or even days, on end; non -compliance by patients diminishes from a major to a minor issue.
  • Electromotive administration of drugs eliminates the most prominent disadvantages of passive transdermal drug delivery.
  • Electromotive Drug Administration is defined as the combined or additive effects of iontophoresis and electrophoresis upon drug transport.
  • iontophoresis is the active transport of ionised molecules into tissue by the passage of an electric current through a solution containing the ions, using an appropriate electrode polarity.
  • the electrical driving force of administration is totally predominant over passive diffusion of the (drug) ions, leading to a greatly accelerated controllable rate of drug administration.
  • iontophoresis is associated with increased transport of water into tissues (electroosmosis) which may induce an enhanced penetration of electrolytes (down their coulombic gradients) and non electrolytes or even the transport of electrolytes against their coulombic gradients, as described by Petelenz et al. (Journal of Controlled Release 1992; 20: 55-66).
  • electrophoresis is a form of "solvent drug" where the gradient of the chemical potential for water activates both a flow of water and of solute dissolved in water.
  • iontophoresis predominates over electrophoresis with ionised drugs as, for example, drugs in the form of their water soluble salts.
  • EMDA of ionised drugs for example of opioids such as of morphine
  • opioids such as of morphine
  • the interval of time required to attain therapeutic blood levels is quite constant for individuals of similiar bodily mass when the same current strengths and times of application are used
  • rates of opioid administration in different individuals depend solely upon the two controllable variables, current and time, not upon the totally uncontrollable vagaries of skin texture and thickness.
  • the feasibility of iontophoretic administration of morphine has been demonstrated in clinical settings by Petelenz et al (U.S. patent No 4,752,285 and 4,915,685); and by Ashburn et al, (J.
  • the second approach was the attachment of the medication (morphine) to an ion exchange matrix so that when the drug ion left the matrix the vacated active sites were occupied by products of electrolysis which was purposely engendered at the anode - drug solution interface (US patent No 4,915,685).
  • EMDA electromotive drug administration
  • Still a further object is that of providing a new morphine formulation which allows for an EMDA with improved efficiency of drug transport.
  • Yet a further object of the invention is that of providing a new morphine formulation for use by EMDA without deleterious changes occurring in the pH of the drug medium during administration and accordingly without damaging the patient's skin.
  • a new formulation of morphine according to the invention comprising one or more morphine citrate salts selected from those having the formula I: M np Ct (3-n) p (C 6 H 5 O 7 ) p wherein M is protonated morphine, Ct is a physiologically acceptable cation, n is any integer or fractional number greater than zero and less than or equal to three (0 ⁇ n ⁇ 3), and p is an integer from 1 to 3.
  • Citric acid has three carboxyl groups, all or part of which can be salified by the morphine base.
  • the formulation of the present invention can comprise trimorphine citrate or mixed citrates of morphine and of a further cation, which is physiologically acceptable, or their mixtures. It is preferred that such further cation be monovalent, since citrate is a weak chelating agent and chelates formed with polyvalent cations could complicate the intended electromotive administration.
  • the further cation is selected from sodium and potassium cations.
  • the morphine citrate according to the invention can be prepared in the form of an aqueous solution, by adding morphine (formula II) for example morphine hydrate in a powder form to a solution of citric acid in such molar quantities that the morphine base is converted to protonated morphine (position 17) such that said conversion results in a solution approximating the formulation: 3M + (C 6 H 5 O 7 ) 3 - .
  • This particular process of the invention may be varied according to circumstances. For example, if the combination results in overt precipitation of morphine base (Mb), two additional procedures, not mutually exclusive, may be employed. They are:
  • citrate salts with said monovalent cations are added.
  • the addition of trisodium (or tripotassium) citrate to a solution of trimorphine (10 mg/ml) citrate admixed with ethanol 20%-30% (v/v) is feasible until the pH reaches 8.0-8.1 units, at which point saturation of ethanol and precipitation of M b will occur.
  • the amount of citrate salt to be added may be varied: the larger the amount added, the greater the buffering capacity.
  • a pure aqueous solution of trimorphine citrate may be additionally buffered by judicious addition of the following combinations, using sodium citrate salts as an example:
  • citrate salts give rise to mixed salts of citrates of morphine and sodium (or potassium) with variable proportions of the cations, as encompassed by the general formula I of morphine citrate salts according to the present invention.
  • charge competition from introduced cations Na + , K +
  • such added citrate salts increased the administration rate of the drug.
  • the morphine citrate solutions prepared as above can have widely variable concentrations, such as from 1 to 80 mg/ml, in particular from 1 to 40 mg/ml. For most purposes a concentration of about 10 mg/ml will be suitable, for example for 12-24 hour post operative analgesia for most patients of all sizes and both sexes.
  • An important point with ionised solutions placed in contact with the skin for the purpose of electromotive delivery, is that they should be preferably hypotonic with respect to the osmolarity of body tissue fluids: hypotonic solutions hydrate the resistive stratum corneum, providing more even distribution of electrical current and lower electrical resistance; hypertonic solutions dessicate the underlying skin, increasing the number of regions of current density and subsequent thermal damage.
  • An isotonic solution of morphine citrate would contain approximate amounts of morphine, 30-80 mg/ml, depending upon the quantity of citrate buffer added.
  • the morphine citrate in addition to its aqueous solution form, can also be formulated in any form in which the morphine ions are free to move.
  • the medicament can be incorporated into a gel (such as gelatin), a hydrogel, a gum, a foam, or a nonionic cream so as to make the iontophoresis process convenient.
  • a gel such as gelatin
  • hydrogel such as gelatin
  • a gum such as a gel
  • a foam such as a nonionic cream
  • the incorporation of the medicament into a cream or gel minimizes the possibility of the drug being improperly extracted from electrodes and misused.
  • the morphine citrate according to the invention is particularly suitable for electromotive administration.
  • the electromotive drug administration (EMDA) technique in this invention relies mainly on iontophoresis, i.e. active transport of ionized drug molecules into the tissue by the passage of electric current with electrophoresis contributing to a lesser, but still important, degree.
  • iontophoresis i.e. active transport of ionized drug molecules into the tissue by the passage of electric current with electrophoresis contributing to a lesser, but still important, degree.
  • the morphine citrate formulation of the invention is administered by a normal iontophoretic device.
  • the drug formulation is placed in a treatment (active) electrode-receptacle wherein the electrode is anodic and is made of substantially inert material.
  • inert anodes usable according to the invention are anodes made of carbon, gold, platinum and stainless steel.
  • the electrically conductive anode is attached to a receptacle so as to form an electrode-receptacle which has to contain the drug solution in contact with the anode and with the patient's skin and avoid leakage of the solution to surrounding areas.
  • the receptacle is usually made of a non-conductive material, for example a polymer, and has a container configuration open at the bottom so as to be positioned on a skin area and to be sealed thereon, for example by adhesive means (tape, ribbon, plaster, etc.) so as to hold a liquid in contact with the respective skin area.
  • a non-conductive material for example a polymer
  • the anode proper can be attached by any appropriate known means to the internal wall of the receptacle so as to come into contact with the drug solution when this latter is introduced into the electrode-receptacle.
  • the anode can be partly embedded in the receptacle side walls, or can be applied as a metal coating on part of the inner surface of the wall, or can be a conductive wire or plaque fixed by any appropriate means to the side wall of the receptacle.
  • Said electrode-receptacle is placed against the skin of the person to be treated and a dispersive, cathodic electrode is also placed on a skin area spaced apart from said treatment electrode.
  • a voltage differential is then applied to the treatment (positive charge) electrode-receptacle and the dispersive (negative charge) electrode.
  • the voltage and current are those commonly used in conventional iontophoretic drug delivery methods.
  • hydrogen ions are produced by hydrolysis of water in the drug solution contained in said treatment electrode.
  • the hydrogen ions are substantially buffered by citrate ions present in the formulation according to this invention, and electromotive forces administer morphine ions transdermally to the person to be treated without deleterious changes in pH occurring in the drug solution contained in the electrode-receptacle.
  • the citrate anion has three pKa levels, 3.13, 4.76 and 6.40 units, which permit a broad selection of pH ranges that can be applied safely to the skin.
  • the three pKa values of the citrate anion permit the formation of a stable ionised salt with morphine whose pKa value is 8.2 units.
  • the morphine citrate formulation according to the invention theoretically attains a much higher efficiency and drug utilization than is possible with the morphine hydrochloride salt used in combination with a silver anode according to the known methods.
  • the Efficiency of drug transport is intended as the percentage of applied electric charge that is utilized in the transport of the drug ions.
  • the efficiency depends, amongst other factors, upon the mobility of the ions present in the drug solution.
  • morphine hydrochloride, MHCl the high molecular weight of morphine (285 daltons) and its consequent low mobility
  • the low molecular weight of chloride (35.5 daltons) and its consequent high mobility give rise, as said before, to a low efficiency of about 9-12%.
  • the molecular weight of the citrate (189 daltons) anion more closely matches that of morphine than does the chloride anion, whereby also its mobility is lower than that of chloride, approaching that of morphine. Consequently, an efficiency of drug delivery higher than 10% can be achieved with morphine in the citrate salt, theoretically up to 30%.
  • the Drug Utilization as defined in this invention essentially refers to the proportion of drug that can be transported from the electrode - receptacle into the skin with continuously running electric current, and without deleterious changes in the rate of drug transport and pH values within the electrode - receptacle.
  • Electromotive utilization of morphine from a solution of morphine hydrochloride with a silver anode is constrained to about 10% by the rapid conversion of chloride ion to insoluble silver chloride precipitate.
  • Phipps et al (US Patent Nos. 4,744,787 and 4,747,819), may be used to calculate the theoretical administration rate of morphine.
  • Rm max 10.6 mg mA -1 h -1 with 100% efficiency of administration.
  • the chloride ion is consumed (converted to AgCl) at about 10 times the rate that morphine ions are administered.
  • Ag + enter the drug solution, reducing still further the efficiency of morphine administration and staining the underlying skin jet black because of reaction with sulphur - containing amino acids: harmless in itself but not appreciated by the subjects. If the supply of silver runs out, the potential rises still further until there is hydrolysis of water, generation of H + and the consequent likelihood of chemical burns to the skin.
  • Phipps et al (US patent No 4,747,819 and 5,057,072) foreshadowed this when they claimed an inert electrode material with an intentionally selected drug in a weak base form and the weak base form of the drug is DOH.
  • a common and useful concentration of morphine is 10 mg/ml or approximately 3.5 x 10 -2 molar. In these concentrations, the hydroxide form of morphine cannot exist in aqueous solution in any appreciable quantities. Hydroxide ions at 3.5 x 10 -2 molar concentrations represent a pH far in excess of the pKa of morphine which would precipitate out as the relatively insoluble, non ionised, base form.
  • Utilization of morphine in morphine citrate solution using an inert anode is constrained only by the decline in pH of the morphine citrate solution: a pH level of 3.5 units is the lower limit of tolerance for human skin. This allows for a much greater morphine utilization than possible according to the prior art.
  • H + generation rate from an inert platinum electrode is approximately 3 x 10 -6 moles mA -1 h -1 .
  • citrate ions in the morphine citrate formulation of the invention had as one of its results the buffering of the hydrogen ions produced at the inert anode and in the maintenance of the pH of the drug solution within acceptable limits for the duration of the drug delivery and thus in the prevention of pH changes deleterious to the patients.
  • Trimorphine Citrate Citric acid powder, 2.1 grams, was dissolved in 1 liter of bidistilled water and the resulting pH of this dilute solution was approximately 3.0 units. To 100 ml of this citric acid solution hydrated morphine base powder (M b ⁇ H 2 O) was added in 100 mg amounts, following each of which additions the mixture was stirred until morphine was completely dissolved and the pH was measured. Following addition of the 10th aliquot (1 gram total) there remained in suspension a small cloud of precipitate and the pH had risen to 6.5-7.0 units. After one hour at room temperature, with the small cloud of precipitate remaining settled at the bottom of the flask, it was resuspended evenly by stirring and shaking and 2.0 ml was withdrawn.
  • Iontophoresis of Morphine Citrate Four volunteers, (RB, RS, DM, CB) underwent preliminary studies with iontophoresis of trimorphine citrate (mc). Conditions were standardised: an iv cannula for blood draws was inserted into the left forearm, the anodic active electrode (carbon) - receptacle containing 4 ml of mc (morphine concentration 9.4 mg/ml) was placed on the anterior aspect of the right forearm near to the elbow and the dispersive electrode on the right forearm near to the wrist. No electric current was used for the initial 30 minutes.
  • Plasma morphine levels were measured in duplicate using a Radio Immune Assay (RIA) technique which is highly specific for free (unconjugated) morphine and has an accuracy of ⁇ 1 ⁇ g/ml.
  • RIA Radio Immune Assay
  • the results are displayed graphically in Figure 1 and, as can be seen, plasma morphine levels were effectively zero prior to beginning electric current, climbed to therapeutic levels ( ⁇ 8 ⁇ g/ml) within 45 minutes in all subjects and then declined when the current was switched off at 60 minutes.
  • Efficiency of morphine administration is calculated from mass balance of morphine in the electrodes pre and post treatments.
  • each electrode contained morphine 4 x 9.4 ⁇ 38 mg total, therefore administration of an average morphine 5 mg defines the percentage administered as 13%.
  • this figure does not represent the utilization as the pH values at the end of one hour were 4.0-4.6 units ( Figure 2) which are above the stated lower limit of 3.5 units. Extrapolation of pH values to 3.5 units indicates a 90 minute cut off in treatment times. Under the same experimental conditions, morphine 7.5 mg will be administered over 90 minutes, which represents a utilization of 20%.
  • Electromotive Administration of M 3 + Na + 3 2(C 6 H 5 O 7 ) 3 - Electromotive administration of M 3 Na 3 (C 6 H 5 O 7 ) 2 in 3 of the 4 previous volunteers, RS, DM, CB, was conducted 5 days after the investigations described above. Experimental conditions were identical except: 1) The current of 2 mA was applied for 2 hours: and 2) blood samples were drawn for 60 minutes post treatment.
  • Plasma levels of morphine are shown in Figure 3 and, as can be seen, morphine blood levels were essentially zero for the first 30 minutes (no current), then reached therapeutic levels within 30 minutes or less following application of electric current and finally plateaued at about 90 minutes.
  • pH levels declined more slowly (Figure 2: mNaC) than in the experiments with trimorphine citrate (Figure 2: mc) and fell from about 6.0 to about 4.5 units over 2 hours of application of electric current at 2 mA.
  • electrophoresis as defined in this invention and which is governed by the coupling of the gradient of a particular species in solution to that of water, is more important than originally anticipated.
  • sodium citrate enhances the negative gradient of chemical potential for water to such a degree that increased electrophoretic transport of morphine more than compensates for the expected decreased efficiency of iontophoretic administration.
  • the term "iontophoresis" is incomplete and only partially accurate when applied to administration of morphine from m(Na)c solutions. Therefore, the inventors have applied the term electromotive drug administration to compensate for this deficency where appropriate.

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Claims (10)

  1. Formulation à base de morphine comprenant un ou plusieurs sels de citrate de morphine, choisis parmi ceux ayant la formule I : Mnp Ct(3-n)p (C6H5O7)p dans laquelle M est de la morphine protonée, Ct est un cation physiologiquement acceptable, n est n'importe quel noire entier ou nombre fractionnaire supérieur à 0 et inférieur ou égal à trois (0<n≤3), et p est un nombre entier de 1 à 3.
  2. Formulation à base de morphine selon la revendication 1, pour l'utilisation par administration par la force électromotrice.
  3. Formulation selon la revendication 1 ou 2, dans laquelle ledit cation est choisi parmi les ions sodium et potassium.
  4. Formulation selon l'une quelconque des revendications 1 à 3, comprenant un citrate de morphine choisi parmi le citrate de trimorphine, le citrate de morphine disodique, le citrate de dimorphine sodique et leurs mélanges.
  5. Formulation selon la revendication 1 ou 2, sous la forme d'une solution aqueuse desdits sels de citrate de morphine ayant une concentration de 1 à 80 mg/ml.
  6. Formulation selon la revendication 5, avant une concentration desdits sels de 1 à 40 mg/ml.
  7. Formulation selon la revendication 5, dans laquelle ladite solution aqueuse comprend en outre 10 à 30 % vol/vol d'éthanol.
  8. Formulation selon la revendication 1 ou 2, comprenant lesdits sels de citrate de morphine incorporés dans un gel, un hydrogel, une mousse ou une crème non ionique.
  9. Procédé de préparation d'une formulation à base de citrate de morphine selon la revendication 1, comprenant les étapes consistant à mélanger de la base de morphine avec de l'acide citrique, éventuellement à ajouter des sels de citrate choisis parmi les citrates acides et neutres de sodium et de potassium, et à empêcher la précipitation de la base de morphine, soit en contrôlant le pH par l'addition d'acide, soit en ajoutant 10 a 30% (vol/vol) d'éthanol à la solution réactionnelle.
  10. Formulation selon la revendication 2, pour l'utilisation avec des anodes sensiblement inertes, choisies parmi l'acier inoxydable, le carbone conducteur, l'or et le platine.
EP93107160A 1993-05-03 1993-05-03 Nouveaux composés de morphine pour administration iontophorétique Expired - Lifetime EP0623345B1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93107160A EP0623345B1 (fr) 1993-05-03 1993-05-03 Nouveaux composés de morphine pour administration iontophorétique
AT93107160T ATE178797T1 (de) 1993-05-03 1993-05-03 Neue morphinzusammensetzungen für iontophoretische verabreichung
DE69324476T DE69324476T2 (de) 1993-05-03 1993-05-03 Neue Morphinzusammensetzungen für iontophoretische Verabreichung
ES93107160T ES2131083T3 (es) 1993-05-03 1993-05-03 Nuevas formulaciones de morfina para su utilizacion por administracion iontoforetica.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP93107160A EP0623345B1 (fr) 1993-05-03 1993-05-03 Nouveaux composés de morphine pour administration iontophorétique

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EP0623345A1 EP0623345A1 (fr) 1994-11-09
EP0623345B1 true EP0623345B1 (fr) 1999-04-14

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AT (1) ATE178797T1 (fr)
DE (1) DE69324476T2 (fr)
ES (1) ES2131083T3 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8097642B2 (en) 1995-02-15 2012-01-17 Boston Scientific Scimed, Inc. Therapeutic inhibitor of vascular smooth muscle cells

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5811447A (en) 1993-01-28 1998-09-22 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US6650934B2 (en) 1996-12-17 2003-11-18 Alza Corp Polymeric foam reservoirs for an electrotransport delivery device
GB9924797D0 (en) 1999-10-20 1999-12-22 West Pharm Serv Drug Res Ltd Compound

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8097642B2 (en) 1995-02-15 2012-01-17 Boston Scientific Scimed, Inc. Therapeutic inhibitor of vascular smooth muscle cells
US8158670B2 (en) 1995-02-15 2012-04-17 Boston Scientific Scimed, Inc. Therapeutic inhibitor of vascular smooth muscle cells

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DE69324476D1 (de) 1999-05-20
EP0623345A1 (fr) 1994-11-09
ATE178797T1 (de) 1999-04-15
DE69324476T2 (de) 1999-09-02
ES2131083T3 (es) 1999-07-16

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